FOsfomycin for E.coli Febrile urinary tract infections as Alternative Stepdown Treatment (FORECAST): Study protocol for a randomized controlled trial Febrile UTI in women

• UTI with systemic symptoms (febrile UTI): • pyelonephritis, urosepsis

• UTIs account for approximately 5 to 7% of all cases of severe sepsis

• Second infectious reason for hospital admittance

• E. coli: major pathogen of community-acquired urinary tract infections (66%)

Geerlings, S. E. Clinical Presentations and Epidemiology of Urinary Tract Infections. Microbiol. Spectr. 4, (2016). Treatment Febrile UTI

• Total antibiotic duration 7-10

• Empirical antibiotic treatment • Oral ciprofloxacin • Intravenous antibiotics if expected ciprofloxacin resistance ≥ 10%

• Stepdown treatment • Oral ciprofloxacin, co-trimoxazole, amoxicillin or augmentin Challenges in stepdown treatment

• Enterobacteriaceae resistance to ciprofloxacin, co- trimoxazole, amoxicillin or augmentin

• Ciprofloxacin restrictive use

• No oral antibiotic option  intravenous antibiotic therapy Resistance in the Netherlands ‘15 2016

Clinical isolates E. coli K. Pneumoniae P. Mirabilis (43%) (7%) (7%)

Antibiotic Ciprofloxacin 13% 6% 9%

Co-trimoxazole 25% 13% 27%

Augmentin 21% 11% 24%

*Nethmap 2015 Fosfomycin

• Phosphoenolpyruvate analogue, Streptomyces spp., produced synthetically

• Inhibiting bacterial cell wall (peptidoglycan) synthesis, dose-effect relationship unknown

• Good safety profile

• Fosfomycin-trometamol: Single dose treatment in women with uncomplicated UTI (Cure +- 90%)

Surber, C. (2016). Product monograph of monurol, (version 4.0). Retrieved from http://www.paladin-labs.com/our_products/Monurol-Sachet-PM-En.pdf Pharmacokinetic profile

Serum Urine

*Bergan, T, Thorsteinsson SB, A. E. (1993). Pharmacokinetic Profile of Fosfomycin Trometamol. Chemo, 39, 297–301 Resistance, following EUCAST

*EUCAST EUCAST E.coli: MIC S<32mg/l>R, CSLI R<64mg/L>R Resistance in the Netherlands ‘15 2016

Clinical isolates E. coli K. Pneumoniae P. Mirabilis (43%) (7%) (7%)

Antibiotic Ciprofloxacine 13% 6% 9%

Co-trimoxazole 25% 13% 27%

Augmentin 21% 11% 24%

Fosfomycin <1% 31% 16%

*Nethmap 2015 Safety

• Little side effects -fosfomycin-trometamol (oral) -intravenous fosfomycin (24 gr/24 hour)

• Tolerability

• Interactions: metoclopramide

• Intoxication Clinical effectivity

Fosfomycin-trometamol Trials Effect Cystitis Meta-analysis RCT* Non-inferior to nitrofurantoin/trimethoprim Complicated UTI Observational studies** Moderate/high effectivity (70-90%)

*Falagas, M. E., Vouloumanou, E. K., Togias, A. G., Karadima, M., Kapaskelis, A. M., Rafailidis, P. I., & Athanasiou, S. (2010). Fosfomycin versus other antibiotics for the treatment of cystitis: A meta-analysis of randomized controlled trials. Journal of Antimicrobial Chemotherapy, 65(9), 1862–1877. doi:10.1093/jac/dkq237

**Giancola, S. E., Mahoney, M. V., Hogan, M. D., Raux, B. R., McCoy, C., & Hirsch, E. B. (2017). Assessment of Fosfomycin for Complicated or Multidrug-Resistant Urinary Tract Infections: Patient Characteristics and Outcomes. Chemotherapy, 100–104. doi:10.1159/000449422 The FORECAST trial:

Randomized controlled, multicentre, double-blind, double- dummy, non-inferior, investigator-initiated trial

To demonstrate non-inferiority of oral fosfomycin compared to oral ciprofloxacin as a step-down treatment for febrile urinary tract infection for the cumulative endpoint survival clinical cure (resolution of symptoms) 6-10 days post-treatment. Inclusion criteria

• Competent women (≥18 years) • Hospitalised • Adequate intravenous antibiotic therapy for ≥48 - ≤120 hours • Candidate for safe iv to oral switch as judged by the attending physician Inclusion criteria

• Urine (≥104 CFU/ml) OR blood culture: Escherichia coli , ciprofloxacin S AND fosfomycin • ≥ local symptom: • lower abdominal pain, low back pain, flank pain or costo-vertebral angle pain or tenderness on physical examination, dysuria, urinary urgency, urinary frequency, suprapubic/pelvic discomfort, macroscopic hematuria, new urinary incontinence or worsening of pre-existing incontinence) • ≥forthcoming systemic symptoms: • Fever/low temperature (≥38.0 C ͦ or <36 C ),ͦ rigors, delirium, hemodynamic instability as a result of sepsis requiring intravenous fluids, increase in CRP (> 30 mg/L) or leucocytes (> 12*10^9/L) • FUTI as presumptive diagnosis and primary reason for hospitalization by attending physician Exclusion criteria

• Pregnant or nursing women • Glomerular filtration rate < 30 ml/min/1,73 m3 or renal replacement therapy • Concomitant systemic antibacterial treatment • Ascertained or presumptive hypersensitivity to the active compounds and/or any excipient of the products or to any quinole • Participation to any trial with an investigational product involved in the 30 days before the screening visit • Specific comorbidity or diagnosis • Patients with inadequate understanding of the study risks or its requirements or unwilling to plan a follow-up visit • Contraindications/interactions for any of the active compounds or medication • Every other laboratory result, clinical condition, disease or treatment that, in investigator’s opinion, make the subject non suitable for the study Intervention

10 days of total antibiotic (iv+oral) treatment, of which 5-8 days of study medication

Duration (hours) ↓ Study arm Control arm 12 H Sachet fosfomycin- Tablet Sachet Tablet trometamol 3g placebo placebo ciprofloxacin 500mg 12 H Tablet Tablet placebo ciprofloxacin 500mg Primary endpoint

The cumulative endpoint survival and clinical cure (resolution of symptoms) 6-10 days post-treatment

Definition: Alive with resolution of local and systemic-related AF-UTI symptoms present at the day of admission, without additional antibiotic therapy Expected endpoint, RCT’s

Trial Population Intervention Bacteremia Cure rate Sandberg 2012 Women with community- Oral ciprofloxacin 2d500mg 7 27% 96 vs 97% acquired pyelonephritis vs 14 days Nieuwkoop 2017 Women with community Ciprofloxacin 2d500mg 7 vs 14 19% 92 vs. 94% acquired pyelonephritis days Sample size calculation

• Expected endpoint: cure rate of 92,5% in ciprofloxacin group vs 92,5% in fosfomycin group • Non-inferiority margin: 10% • Power (ß-1): 80% • Alpha (type I error), two-sided: 5% • Sample size needed: 109 per group • Accounting for 10% of lost participants = 120 per group = N=240 Secondary endpoints Time (days) Microbiological cure (y/n) 6-10 Fosfomycin resistance (y/n), ciprofloxacin resistance (y/n), ESBL-producing 6-10 bacteria (y/n) in urine culture Early study medication discontinuation 6-10 Survival and clinical cure 30-35 Mortality (y/n) 30-35

ICU admissions 30-35 Readmissions (y/n) 30-35

Relapses (y/n) 30-35

Reinfections (y/n) 30-35

Additional antibiotic use (y/n) 30-35

Hospitalization (days)* 30-35

Study protocol related adverse events (y/n) 30-35

*Except earlier scheduled admissions Logistics Empirical intravenous antibiotic treatment Admittance Daily query GLIMS E.coli urine/blood culture Informed consent Stratification per study Randomization centre

Study treatment Study arm (fosfomycin) Control arm (ciprofloxacin)

Evaluation (1) 6-10 days post-treatment 6-10 days post-treatment

Evaluation (2) 30-35 days post-treatment 30-35 days post-treatment